Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor, erythroid 2 related factor 2 (Nrf2) belongs to the Cap'n'collar/basic region leucine zipper (CNC-bZIP) transcription factor family, and is activated by diverse oxidants, pro-oxidants, antioxidants, and chemopreventive agents. After phosphorylation and dissociation from the cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), Nrf2 translocates to the nucleus and binds to an antioxidant response element (ARE). Through transcriptional induction of ARE-bearing genes that encode antioxidant-detoxifying proteins, Nrf2 activates cellular rescue pathways against oxidative injury, inflammation/immunity, apoptosis, and carcinogenesis. ARE-driven genes include direct antioxidants (e.g., GPx), thiol metabolism-associated detoxifying enzymes (e.g., GSTs), stress-response genes (e.g., HO-1), and others (e.g., PSMB5). Application of nrf2 germ-line mutant mice elucidated protective roles for Nrf2 in various models of human disorders in the liver, lung, kidney, brain, and circulation. In the lung, deficiency of nrf2 augmented injury caused by bleomycin and environmental oxidants including hyperoxia, diesel exhaust particles, and cigarette smoke. Microarray analyses of lungs from nrf2-deficient and -sufficient mice identified Nrf2-dependent genes that might be critical in pulmonary protection. Observations from these studies highlight the importance of the Nrf2-antioxidant pathway and may provide new therapeutic strategies for acute respiratory distress syndrome, idiopathic pulmonary fibrosis, cancer, and emphysema in which oxidative stress is implicated.
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PMID:Nrf2 defends the lung from oxidative stress. 1648 40

Disruption of NF-E2-related factor (Nrf2), a redox-sensitive basic leucine zipper transcription factor, causes early-onset and more severe emphysema due to chronic cigarette smoke. Nrf2 determines the susceptibility of lungs to cigarette smoke-induced emphysema in mice through the transcriptional induction of numerous antioxidant genes. The lungs of Nrf2-/- mice have higher oxidative stress as evident from the increased levels of lipid peroxidation (4-hydroxy-2-nonenal) and oxidative DNA damage (7,8-dihydro-8-Oxo-2'deoxyguanosine) in response to cigarette smoke. Glutathione peroxidases (GPX) are the primary antioxidant enzymes that scavenge hydrogen peroxide and organic hydroperoxides. Among the five GPX isoforms, expression of GPX2 was significantly induced at both mRNA and protein levels in the lungs of Nrf2+/+ mice, in response to cigarette smoke. Activation of Nrf2 by specific knock down of the cytosolic inhibitor of Nrf2, Keap1, by small inhibitory RNA (siRNA) upregulated the expression of GPx2, whereas Nrf2 siRNA down-regulated the expression of GPX2 in lung epithelial cells. An ARE sequence located in the 5' promoter-flanking region of exon 1 that is highly conserved between mouse, rat, and human was identified. Mutation of this ARE core sequence completely abolished the activity of promoter-reporter gene construct. The binding of Nrf2 to the GPX2 antioxidant response element was confirmed by chromatin immunoprecipation, electrophoretic mobility shift assays, and site-directed mutagenesis. This study shows that GPX2 is the major oxidative stress-inducible cellular GPX isoform in the lungs, and that its basal as well as inducible expression is dependent on Nrf2.
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PMID:Glutathione peroxidase 2, the major cigarette smoke-inducible isoform of GPX in lungs, is regulated by Nrf2. 1743 Oct 99

Tobacco may be involved in the decreased macrophage heme oxygenase-1 (HO-1) expression described in smoking-induced severe emphysema, via the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-BTB and CNC homology 1, basic leucine zipper transcription factor 1 (Bach1) pathway. We assessed in vitro effects of cigarette smoke condensate (CS) in the human monocyte/macrophage cell line (THP-1). CS exposure led to increased HO-1 and nuclear Nrf2 expression (6 h) followed by decreased HO-1 expression concomitantly with nuclear Nrf2/Bach1 ratio decrease (72h). CS-induced mitogen-activated protein kinase (MAPK) phosphorylation. Extracellular-signal-regulated kinase(1/2) (ERK(1/2)) and c-Jun NH2-terminal kinase (JNK) inhibition completely abrogated CS effects on HO-1 expression and nuclear Nrf2/Bach1 translocation. These results suggest that ERK(1/2) and JNK are involved in CS-induced biphasic HO-1 expression by a specific regulation of Nrf2/Keap1-Bach1.
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PMID:Prolonged cigarette smoke exposure decreases heme oxygenase-1 and alters Nrf2 and Bach1 expression in human macrophages: roles of the MAP kinases ERK(1/2) and JNK. 1982 48

Chronic exposure to cigarette smoke (CS) generally confronts cellular defense systems with one of the strongest known environmental challenges. In particular, the continuous exposure of tissues of the respiratory tract to abundant concentrations of radicals; volatile compounds of the gas phase, mainly reactive oxygen and nitrogen species; and CS condensate deposits trigger a pleiotropic adaptive response, generally aimed at restoring tissue homeostasis. As documented by numerous studies published over the past decade, a hallmark of this defense system is the activation of the transcription factor NF-E2-related factor 2 (Nrf2), which, consequent to its established role as master regulator of the cellular antioxidant response, has been shown to orchestrate the first line of defense against cell- and tissue-damaging components present in CS. The key to CS-dependent Nrf2 activation is assumed to be based on the long-known phenomenon of a general strong sulfhydryl (-SH) reactivity inherent to CS. This chemical trait is virtually predestined to be sensitized by the major route leading to Nrf2 activation, characterized by its dependence on the interaction of electrophiles with specific cysteine residues inherited by Nrf2's negative cytosolic regulator Keap1 (Kelch-like ECH-associated protein 1). In addition, other pathways involving CS-activated protein kinases implicated in the upstream regulation of Nrf2, such as protein kinase C, represent an alternative/complementary mechanism of CS-induced Nrf2 activation. Because of the outstanding function of the Nrf2-Keap1 axis in defending cells and tissues against oxidant and chemical stress, either directly or indirectly via cross-talking with other defense pathways, changes in the Nrf2 or Keap1 genotype have long been associated with disease development. In terms of the two major smoking-related diseases of the lung, that is, emphysema and lung cancer, a fully functional Nrf2 genotype seems to be necessary, although not sufficient by itself, to protect the smoker from acquiring emphysema. Contrasting with this protective role, however, Nrf2 function may be potentially fatal in smoking-related lung tumorigenesis: as concluded from recent clinical investigations, lung tumor tissues harbor increased mutation or, alternatively, aberrant expression rates in either the KEAP1 or the NRF2 gene, generally resulting in constitutive Nrf2 activation, suggesting that "abuse" of Nrf2 function is an advantageous strategy of the (developing) tumor to protect itself against oxidative stress in general. On the basis of the fundamental significance of the Nrf2 pathway in smoking-dependent disease development, several attempts have been described for dietary and pharmacological intervention, the majority of which are intended to activate Nrf2 aiming at emphysema prevention. The intention of this review is to compile and discuss the various aspects of CS-Nrf2/Keap1 interaction in terms of mechanism, disease development, and chemoprevention.
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PMID:Nrf2: friend and foe in preventing cigarette smoking-dependent lung disease. 2268 25